The IL-17 cytokine family, consisting of six subtypes A-F, is known to be involved in autoimmune disease, inflammatory disease and cancer. To date, however, the role of these cytokines in tumor-immunity remains unclear with studies showing conflicting results. Moreover, whereas, IL-17A/F have been heavily investigated, the role of IL-17D in antitumor immunity is not yet characterized. Our laboratory has recently identified a novel role for the cytokine IL-17D as an important mediator of the antitumor immune response, and the loss of IL-17D as a key component of tumor progression. A microarray screen conducted in our laboratory to compare immunogenic to non-immunogenic sarcomas identified a significantly different expression of the cytokine IL-17D among the tumor types. Our preliminary data show for the first time that overexpression of the cytokine IL-17D is sufficient t mediate tumor rejection. We have also found that IL-17D can be induced by oxidative stress signals via the transcription factor Nrf2. [Based on these data, I will examine the requirement for IL-17D in tumor surveillance using primary carcinogenesis models, the regulation of IL-17D during carcinogenesis, and the efficacy of IL-17D as an immune therapeutic. First, I will examine the role of IL-17D in the immunosurveillance of primary tumors in vivo, using WT and IL-17D-/- mice and three well-studied models in our laboratory: MCA-induced sarcomas, DMBA/TPA-induced papillomas, and PYMT-induced breast cancer. Second, I will characterize the upstream events that induce IL-17D expression with focus on the transcription factor, Nrf2. I will accomplish this by comparing the activity of Nrf2 between certain immunogenic tumors, which express IL-17D, and poorly immunogenic tumors, which do not. This will accomplish the short-term goal to understand why some tumors have constitutive expression of IL-17D whereas others lack it and the long-term goal to understand the regulation and endogenous function of IL-17D. Subsequently, I will determine the induction of IL-17D and Nrf2 in cells undergoing transformation in vivo using primary mouse models of cancer. Third, I will determine the potential of IL-17D in combination therapy for treating established tumors. I will treat establishe transplantable sarcoma and melanoma tumors with IL-17D as monotherapy or in combination with other immunotherapeutics or immumoactivators, with which I hypothesize IL-17D will mechanistically synergize. Specifically, IL-17D will be induced (via an inducible gene system) or injected intratumorally in combination with treatments such as aCTLA4/aPD1. Some mice will be treated with tBHQ, a reagent that can induce Nrf2. The growth and development of these transplanted tumors will be assessed, and the tumor-infiltrating immune cells will be phenotyped in order to analyze the effects that IL-17D has in enhancing anti-tumor immune responses.]